The goal of the proposed R03 project is to develop novel, potent hTAAR1 antagonists with good drug-like properties that can be used as therapeutics for Parkinson?s Disease (PD). PD is an incurable, multi-system, progressive neurodegenerative disorder that affects ~0.3% of the worldwide aging population. PD is neuropathologically characterized by the loss of dopaminergic (DAergic) neurons in the substantia nigra pars compacta (SNpc) mid-brain region. This resulting DA deficiency leads to the development of motor (rigidity, resting tremor) and non-motor symptoms (depression, anxiety, dementia). Current therapies target PD symptoms and focus on increasing brain DA levels or stimulating DA receptors in an effort to correct motor dysfunction. Currently, the DA pro-drug L-DOPA provides the greatest symptomatic benefit early on but causes motor complications (dyskinesias), shorter duration of response, and fluctuations of good and poor responses. Although much research is being conducted to identify new PD therapeutics, there is an unmet need for therapeutics that can reduce the rate of neurodegeneration or stop the disease progression. The human Trace Amine-Associated Receptor subtype 1 (hTAAR1) is a G protein-coupled receptor that is activated by endogenous trace amines and is widely expressed in monoaminergic nuclei in the brain, including the SNpc, the brain region most affected by PD. Studies have shown that blocking TAAR1 activity results in increased DAergic signaling and neuronal firing in the brain, increased efficacy of L-DOPA, and decreased neurodegeneration in a PD mouse model. Because there are currently no potent hTAAR1 antagonists available, it is critical to identify such compounds to probe alternative or adjuvant PD therapies. Through our preliminary research, we have identified a potent hTAAR1 antagonist, TAR-44, that is 701-fold more potent (hTAAR1 IC50 = 10.7 nM) than the only well characterized hTAAR1 antagonist in the literature (EPPTB IC50 = 7.5 ?M). The proposed R03 project will use a combination of medicinal chemistry and pharmacology approaches to develop novel, potent hTAAR1 antagonists based on the TAR-44 scaffold with good drug-like properties. In Aim 1, we will perform a structure activity relationship analysis of the TAR-44 scaffold and synthesize 50 analogs. In Aim 2, the synthesized compounds will be evaluated for hTAAR1 antagonist potency and species selectivity. Selected compounds will be further evaluated for preliminary ADME properties (solubility, blood-brain barrier permeability, and metabolic stability) and off-target effects (NIMH Psychoactive Drug Screening Program).